Comprehensive computational analysis of genetic and regulatory differences between individuals with African and European ancestries across four brain regions

对四个大脑区域的非洲和欧洲血统个体之间的遗传和监管差异进行全面的计算分析

• 批准号: 10532304
• 负责人: Kynon Jade M Benjamin
• 金额: $ 9.71万
• 依托单位: LIEBER INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532304
• 关键词: Address; Affect; African ancestry; Antipsychotic Agents; Autopsy; Brain; Brain Diseases; Brain region; Career Transition Award; Cells; Collaborations; Collection; Complex; Computer Analysis; DNA Methylation; Data; Data Set; Development; Disease; Disease susceptibility; Disparity; Environment; Epigenetic Process; Equity; European ancestry; Exons; Explosion; Future; Genes; Genetic; Genetic Transcription; Genetic Variation; Genomics; Genotype; Goals; Grant; Heritability; Hippocampus; Human; Human Genetics; Individual; Life; Link; Machine Learning; Maps; Mental Health; Mental disorders; Mentors; Mentorship; Methods; Methylation; Modeling; Neurosciences; Phase; Play; Postdoctoral Fellow; Prefrontal Cortex; Quantitative Trait Loci; Reduce health disparities; Research; Research Personnel; Research Project Grants; Resource Development; Role; SNP array; Sampling; Schizophrenia; Statistical Methods; Techniques; Testing; Training; Transcript; Universities; Variant; Work; biological research; bisulfite sequencing; brain tissue; career; career development; caudate nucleus; causal variant; cell type; cohort; data integration; dentate gyrus; diagnostic accuracy; differential expression; drug discovery; epigenetic variation; experience; experimental study; fetal; follow-up; genetic analysis; genomic data; health disparity; improved; indexing; nervous system disorder; neurodevelopment; neuropsychiatric disorder; personalized medicine; postnatal; prenatal; response; skills; success; trait; transcriptome sequencing; whole genome

Project Summary / Abstract Health disparities have endured for centuries. The disparity in research for biological variations is even greater, where the explosion of genetic and environmental data has focused almost exclusively on those of European ancestry (EA). In neuroscience and genomics, individuals with recent African ancestry (AA) account for less than 5% of large-scale genomic studies but are 20% more likely to experience a major mental health crisis. To compound this issue further, studies have linked genetic differences between AA and EA for divergent responses to antipsychotics. As a result, large-scale studies for neuropsychiatric disorders have limited diagnostic accuracy for non-European ancestry individuals, hindering the development of effective equitable neurotherapeutics and potentially increasing health disparities. Despite the clear urgent need, there are no large-scale studies examining genetic or regulatory differences between AA and EA in the human brain. This proposal seeks to address this gap in research by comparing AA with well-studied EA individuals. The initial goal of this proposal is to identify genetic and regulatory difference between AA (n=784) and EA (n=678) in postmortem caudate nucleus (n=420), dentate gyrus (n=161), dorsolateral prefrontal cortex (n=434), and hippocampus (n=447), compiled from one of the largest postmortem brain collections of psychiatric disorders. This diverse large-scale postmortem brain tissue will allow us to test the hypotheses of genetic variations influence on brain region-specific transcriptional and epigenetic changes for ancestry across prenatal and postnatal life. This MOSAIC (Maximizing Opportunities for Scientific and Academic Independent Careers) Postdoctoral Career Transition Award to Promote Diversity will be supported by excellent career development resources at the Lieber Institute for Brain Development and Johns Hopkins University, and training from a mentoring team of globally recognized experts in the fields of human genetics and advanced statistical methods. It will provide a first of its kind examination of ancestry in neuroscience, which will advance our understanding of genetic variation in the human brain.

项目概要/摘要 健康差距已经持续了几个世纪。对生物变异的研究差距更大， 遗传和环境数据的爆炸式增长几乎完全集中在欧洲的数据上 血统（EA）。在神经科学和基因组学中，具有近代非洲血统（AA）的个体所占比例较低 超过 5% 的大规模基因组研究，但经历重大心理健康危机的可能性高出 20%。到 使这个问题进一步复杂化的是，研究已将 AA 和 EA 之间的遗传差异联系起来 对抗精神病药物的反应。因此，针对神经精神疾病的大规模研究有限。 非欧洲血统个体的诊断准确性，阻碍了有效公平的发展 神经治疗和可能增加的健康差距。尽管有明显的迫切需要，但没有 大规模研究检查人脑中 AA 和 EA 之间的遗传或调节差异。这 该提案旨在通过将 AA 与经过充分研究的 EA 个体进行比较来解决研究中的这一差距。最初的 该提案的目标是确定 AA (n=784) 和 EA (n=678) 之间的遗传和监管差异 死后尾状核 (n=420)、齿状回 (n=161)、背外侧前额皮质 (n=434) 和 海马体（n = 447），由最大的精神疾病死后大脑收藏之一汇编而成。 这种多样化的大规模死后脑组织将使我们能够测试遗传变异的假设 产前和产后对大脑区域特异性转录和表观遗传变化的影响 产后生活。这个 MOSAIC（科学和学术独立职业机会最大化） 促进多元化的博士后职业转型奖将得到优秀职业发展的支持 利伯大脑发育研究所和约翰霍普金斯大学的资源，以及来自 由人类遗传学和高级统计领域全球知名专家组成的指导团队 方法。它将首次对神经科学的祖先进行检查，这将推动我们的进步 了解人类大脑中的遗传变异。